Student Old Dominion Univ., Virginia, United States
Disclosure(s):
Shelby Ma, MS: No financial relationships to disclose
Introduction/Rationale: Atherosclerosis is an inflammatory disease characterized by plaque buildup in vessels. Cholesterol homeostasis is crucial to prevent toxic cholesterol levels, but it is often dysregulated in hyperlipidemic states. Desmosterol, a cholesterol precursor, inhibits macrophage activation. While the impact of cholesterol metabolism on macrophage functions is well-studied, its role in regulating B cell functions remains unclear.
Methods: We generated atherosclerosis-prone Dhcr24fl/flCd19cre/+Ldlr-/- mice, in which B cells overexpress 24-dehydrocholesterol reductase (DHCR24), an enzyme that converts desmosterol into cholesterol. DHCR24 overexpression depleted desmosterol levels in B cells from Dhcr24fl/flCd19cre/+Ldlr-/- vs Cd19cre/+Ldlr-/- control mice. To test the impact of desmosterol depletion in atherogenesis, Dhcr24fl/flCd19cre/+Ldlr-/- and Cd19cre/+Ldlr-/- mice were fed a high-fat diet (HFD) for 12-16 weeks.
Results: Desmosterol-depleted B cells from HFD-fed Dhcr24fl/flCd19cre/+Ldlr-/- show increased mitochondrial superoxide production, elevated Ca2+ flux and pSYK in the response to anti-IgM-induced BCR activation vs B cells from Cd19cre/+Ldlr-/- mice. Desmosterol depletion in B cells increased lipid loading and shifted GC formation, which was accompanied by a decline in mitochondrial function of B cells from HFD-fed Dhcr24fl/flCd19cre/+Ldlr-/- mice. Importantly, Dhcr24fl/flCd19cre/+Ldlr-/- mice also increased atherogenesis vs Cd19cre/+Ldlr-/- mice.
Conclusion: Together, this suggests that desmosterol acts as a suppressive regulator of B cell activation, influencing their functions. This highlights a previously unrecognized role of desmosterol in modulating B cell responses in atherosclerosis.
